LPS-induced monocarboxylate transporter-1 inhibition facilitates lactate accumulation triggering epithelial-mesenchymal transformation and pulmonary fibrosis

Cell Mol Life Sci. 2024 May 6;81(1):206. doi: 10.1007/s00018-024-05242-y.

Abstract

The epithelial-mesenchymal transformation (EMT) process of alveolar epithelial cells is recognized as involved in the development of pulmonary fibrosis. Recent evidence has shown that lipopolysaccharide (LPS)-induced aerobic glycolysis of lung tissue and elevated lactate concentration are associated with the pathogenesis of sepsis-associated pulmonary fibrosis. However, it is uncertain whether LPS promotes the development of sepsis-associated pulmonary fibrosis by promoting lactate accumulation in lung tissue, thereby initiating EMT process. We hypothesized that monocarboxylate transporter-1 (MCT1), as the main protein for lactate transport, may be crucial in the pathogenic process of sepsis-associated pulmonary fibrosis. We found that high concentrations of lactate induced EMT while moderate concentrations did not. Besides, we demonstrated that MCT1 inhibition enhanced EMT process in MLE-12 cells, while MCT1 upregulation could reverse lactate-induced EMT. LPS could promote EMT in MLE-12 cells through MCT1 inhibition and lactate accumulation, while this could be alleviated by upregulating the expression of MCT1. In addition, the overexpression of MCT1 prevented LPS-induced EMT and pulmonary fibrosis in vivo. Altogether, this study revealed that LPS could inhibit the expression of MCT1 in mouse alveolar epithelial cells and cause lactate transport disorder, which leads to lactate accumulation, and ultimately promotes the process of EMT and lung fibrosis.

Keywords: Epithelial-mesenchymal transformation; Lactate; Lipopolysaccharide; Monocarboxylate transporter-1; Pulmonary fibrosis.

MeSH terms

  • Alveolar Epithelial Cells / drug effects
  • Alveolar Epithelial Cells / metabolism
  • Alveolar Epithelial Cells / pathology
  • Animals
  • Cell Line
  • Epithelial-Mesenchymal Transition* / drug effects
  • Lactic Acid* / metabolism
  • Lipopolysaccharides* / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Monocarboxylic Acid Transporters* / antagonists & inhibitors
  • Monocarboxylic Acid Transporters* / genetics
  • Monocarboxylic Acid Transporters* / metabolism
  • Pulmonary Fibrosis* / chemically induced
  • Pulmonary Fibrosis* / metabolism
  • Pulmonary Fibrosis* / pathology
  • Symporters* / antagonists & inhibitors
  • Symporters* / genetics
  • Symporters* / metabolism
  • Up-Regulation / drug effects

Substances

  • Monocarboxylic Acid Transporters
  • monocarboxylate transport protein 1
  • Lipopolysaccharides
  • Symporters
  • Lactic Acid